Epidemic keratoconjunctivitis (EKC) is a serious and contagious eye infection (conjunctiva and cornea) caused by the adenoviruses HAdV-8, HAdV-19, and HAdV-37 of speciesHAdV-D, and HAdV-4 of speciesE.
Furthermore, HAdV-53 of species D has also been reported to cause EKC (PLoS One, 2009, 4(6), 1-14, doi:10.1371/journal.pone.0005635.g001). In addition, a adenovirus denoted HAdV-22,37/H8 have been isolated from patients with EKC.
Recently, a virus denoted HAdV-54 has also been reported to cause EKC. (British Journal of Ophthalmology (2010) Hisatoshi Kaneko et al, “Epidemiological and virological features of epidemic keratoconjunctivitis due to new human adenovirus type 54 in Japan” published online Jun. 8, 2010, doi: 10.1136/bjo.2009.178772)
The symptoms of EKC are inflammation in the conjunctiva (conjunctivitis) and in the cornea (keratitis), pain, edema, diminished eye sight, tearing, sensitivity to light, feeling of a foreign body in the eye and development of pseudo membranes. During the acute phase of the disease (approximately two to three weeks), viruses are present and replicating. One of the eyes is normally infected first and it spreads to the other eye within two to three days. The infection in the first eye is normally more serious. In approximately 30% of patients' corneal opacities that result in deteriorating eye vision remains for weeks, months, or even years.
Since the disease is often epidemic in nature, it is called epidemic keratoconjunctivitis (EKC).
The patient is unable or is recommended by a doctor not to go to work or school due to the symptoms and the highly contagious nature of the disease. Approximately 45% of people in the patient's close surroundings, e.g., family members, become infected. The recurrence rate is 25% (within five years) after a first infection and 50% after a second.
EKC is transferred between individuals via physical contact, e.g. from eye to hand, from hand to a door knob, from door knob to another person's hand, and then to an uninfected eye. Viruses causing EKC can survive on e.g. door knobs, towels etc. for months. Adequate infection control measures must be followed in order to prevent and reduce epidemic outbreaks.
Treatment of the acute phase of the infection with topical steroids has been widely used. However, recent findings conclude that steroids may prolong the persistence in the cornea and frequent use may lead to long-lasting dry eye symptoms. The recommendation is that steroids should be avoided in both the acute and the chronic phase of the disease.
This highly contagious disease can be found all over the world, but is more common in heavily populated countries in Asia. Adenovirus conjunctivitis is particularly problematic in Japan where about one million cases of EKC is reported each year.
EKC occurs worldwide sporadically and epidemically and is endemic in East Asia, including Japan, Korea and Taiwan. It has gained recognition as a major health problem in these regions. The economic and social costs of this community epidemic are also high. Work places, public institutions, such as schools and children's day care centers', must be closed following the outbreak of an epidemic. Many work hours are lost every year as a consequence of the disease.
Although EKC normally heals up within 2 to 3 weeks, the costs to society in terms of both health care costs and loss of production because of its highly contagious nature are very substantial. The disease also has long-term implications for eyesight and recurrence.
The adenoviruses causing the EKC interact with their cellular receptors through fiber proteins that extend from the virus particle. Each particle has 12 homotrimeric fiber proteins, and thus, the receptor binding domain of the fiber (the knob) presents three separate binding sites.
The cellular receptor of HAdV-37 has been found to be a glycoconjugate carrying at least one terminal sialic acid moiety linked through an α2,3, glycosidic bond to the neighboring saccharide chain. Thus, the ability of adenoviruses HAdV-8, HAdV-19, HAdV-37, and presumably also other adenoviruses causing severe forms of EKC, such as HAdV-53, HAdV-54, and HAdV-22,37/H8, is strongly associated with their ability to bind to sialic acid on the cell surface. An antiviral drug based on sialic acid may therefore have the potential to block viral attachment. Accordingly, such a drug may possibly be used to treat patients suffering from EKC. Furthermore, it may possibly be used to prevent EKC.
WO 01/037846 discloses that adenoviral infections and in particular ocular adenoviral infections, e.g. kerato-conjunctivitis, may be treated or alleviated by the administration of a substance, interfering with the interaction between the virus and the sialic acid receptor, such as sialic acid, in a therapeutically effective amount.
Unfortunately the weak interactions between carbohydrates and proteins limit the use of carbohydrates as drugs. Attempts to overcome said limitations have been made (Johansson, S. M. C., et al Antiviral Research 73 (2007) 92-100) by using a glycoconjugate with several sialic acid derivatives linked to human serum albumin (SA-HSA).
However, such polyvalent glycoconjugates are for several reasons not suitable as pharmaceuticals.
The exact structure and composition of SA-HSA will vary between different molecules. Accordingly, SA-HSA represents a type of structure which is hard to structurally define. Furthermore, the composition of the SA-HSA derivatives will vary between different batches even if produced in the same manner. From a safety and a regulatory perspective this is a significant drawback.
In addition the use of a protein, i.e. HSA, which is derived from human plasma, is a major disadvantage. The origin of HSA makes it hard to produce larger amounts of a pharmaceutical based on HSA. Furthermore, contamination by infectious agents, such as viruses or prions, may not be excluded in HSA derived from human plasma.
Accordingly, a product based on HSA, is not suitable as a pharmaceutical product, and a polyvalent alternative would be highly desirable.
Currently, no clinically applicable specific antiviral therapy is available to shorten the course of the infection, to improve the distressful clinical symptoms, to stop viral replication, or to prevent the development of corneal opacities.
Accordingly, EKC is a disease where there is a lack of effective treatment and a large unmet medical need. A pharmaceutical that could be used for the treatment of EKC as well as for the prevention of its spread would be therefore highly desirable.